Angiogenesis is the process whereby new blood vessels are formed from preexisting vessels; it is a highly regulated event that encompasses a coordinated cascade of gene expression and repression, and one that is influenced by many factors, including a variety of environmental cues provided by the extracellular matrix (ECM) (Sottile, 2004; Stupack and Cheresh, 2002). Cancer cells play a vital role in eliciting many of these environmental cues in part via their ability to produce and secrete numerous angiogenic factors and proteases that create tumor microenvironments conductive to angiogenesis (Bissell et al, 2002; Pupa et al, 2002; Sottile, 2004). Although previously believed to be innocent bystanders during angiogenic reactions, it is becoming increasingly apparent that endothelial cells (ECs) also make important contributions to the activation and resolution of angiogenesis. Indeed, ECs generate a variety of environmental cues that shape and remodel tumor and vascular microenvironments, ultimately leading to altered vessel development (Davis and Senger, 2005; Sottile, 2004). Unfortunately, the molecular mechanisms whereby ECs and the molecules they secrete actively direct angiogenesis activation and resolution remain to be determined definitively. It is known that tumor angiogenesis depends upon the coordinated cooperation between cancer and endothelial cells (ECs), and results in the formation and infiltration of new vessels into tumor microenvironments, thereby providing developing tumors with a source of nutrients and oxygen, as well as a route for cancer cell metastasis (Carmeliet and Jain, 2000; Folkman and Shing, 1992). Failure to establish these cancer:EC connections prevents the development and progression of small, innocuous cancer growths, and as such, tumors remain in a dormant, benign state (Bergers and Benjamin, 2003; Hanahan and Folkman, 1996). Recently, significant inroads in understanding of the role of cancer cells in mediating tumor angiogenesis and EC activation have taken place. Indeed, cancer cells actively induce tumor angiogenesis via their ability to produce and secrete a variety of pro-angiogenic factors (Liotta and Kohn, 2001; Stupack and Cheresh, 2002), a process known as the angiogenic switch (Bergers and Benjamin, 2003; Hanahan and Folkman, 1996). In contrast, comparably little is known concerning the role of ECs during this process, particularly the functional consequences of their ability to remodel vascular and tumor microenvironments during angiogenesis. Although ECs are known to remodel their microenvironment by secreting various extracellular proteases, such as MMPs (matrix metalloproteases), ADAMs (a disintegrin and metalloprotease domain), and ADAMTS (a disintegrin and metalloprotease domain with thrombospondin motifs; Stupack and Cheresh, 2002), a thorough understanding of how these molecules and their stromal targets mediate angiogenesis activation or resolution remains incompletely understood. Thus, identifying and characterizing novel proteins secreted by angiogenic ECs will offer important insights into the role of the endothelium in mediating angiogenesis, as well as its potential to be targeted therapeutically to prevent tumor angiogenesis. Specifically, mapping and defining the EC secretome will significantly enhance understanding of angiogenesis, as well as identify novel therapeutic agents and/or targets that can be exploited to prevent tumor angiogenesis and metastasis in cancer patients.